Dibasic acids and salts thereof



I im S w Patent @fiice 3,@Z3,Z3Z Patented Feb. 27, 1962 3,023,232 J IC AER DS- AND SALT THEREQF mit lin nm, Fer u on Mir-i a s gn-9r t Ma iinekrodt Chemical Works, St. Louis, Mo, acorporaw tion of Missouri H i No Drawing. Filed Dec 21,1956, Ser. No. 629,780 8 Claims. (Ci. 2'60---513) the alpha-amino group. v

More particularly," the invention is directed to; the novel class of dibas ic organic acids represented by the general formula; r

in which R is a lower alkylene radicaliselectedifrom, the group consisting of methylene, polymethylene, and alkylsubstituted methylene radicals, and: A. is; a, monobasic, organic acid radical selectedfromthe group; consis in of-"carboxyl and sulfonic radicals, and the salts thereof; and to aminoacid; derivatives;of'dith-ipoxamide haying; the formula:

R o o-HR II II S S which R represents a radical derived from an aliphatic iha-amino acid by reinovaliof a hydrogen atomfrom 18 alpha-amino group. The present invention also in- ;ludes novel methods for preparing N,N '-dithioox-alylbisaminoacids andtheir salts.

Among the objectsof this invention are the-provision. of new dibasic acids; the provision of compounds-of: the type indicated which are derivatives-of dithiooxarnide; the provision of compounds-j of the; type indicated which contain a plurality of functional groups; the provision of compounds of, the type indicated which are useful intermediates for the preparationof'othercompounds: of"related structure; the provision of improved chelating: 50

agents; the provision of improved-dyes,- the-provision of) improved toners for photographicprint-s; the-provision of improved d-iureticsi and the provisionof methods forpreparing compounds of the type referredto-which arei efficient and economical. Otherobjects and-features will be in part apparent and in part pointed out herein-after, The invention accordingly comprisesthe products. and

- methods hereinafter described, the-scope-of the inventionbeing indicated-in thefollowing"c lairns .t

- In accordance with the "present invention, it: has been found hat" the novel N;N d-ithiooxalylbis-anlino'acidsrepresented by the formula:

stituted methylene and polymeth y-l-ene; radicals, and: A- is;

a monob sic acid radical, and-the salts thereof. possess many useful a-ndvalua-ble properties. "includedainongthe acids of this novel group of compounds are, forexarnple,"

HOOCCH NHGSCSNHCH COOH and; NN -dithiooxa y b sram n alka es lfo ie, a ids, su h as N,N'-dithiooxalylbis-Z-aminoethanesulfonic acid,

The compounds-of this invention also include salts of these acids, such as, for. example, the-sodium, nickel, cobalt; and when alt Arnong the useful properties of; the novel acids of the nv t n is hep n o low ng s i a d s s sx compounds with metallicions. Many of these compounds, such as those formed with iron, nickel, cobalt, and: copper are useful, for. example asytextile, dyes Or; toners; for photographic 'printsf In addition, certain, of, the N,Nf-dithiqox alylbis-aminoallganpic acids of this. in,- vention possess surprising and, valuable physiological properties, In particular, it. has been; found, that N,N dithiooxalylbisaminoacetic acid, N,Nv-dithiooxalylbisa2e aminobutanoic acid; N,N-dithiooxalylbis-4-aminobutar, note acid and; Niflf-dithiooitalylbis-2-aminopentanoic acid are effective diuretics, Moreover, they display. alovm orderof toxicity at= dosage levels which provide significant diuretic action.

It is, well, known, that, primary aliphatic amines react with, dithiooxarnide rather readily. However, when a} similar, reaction. is attemtgted usingan amino acidinstead of an amine, little or no reaction takes place, Ithasnoyv, been found, however, in accordanoe with the present invention, that when dithiooxamide is heated in a suitable inert mediumwith a saltofi a monobasic amino acid such as, for. example, an aminoallganoic. acid, or an, aminoalkanesulfonic acid, the tworeactantscondense-to form-aalt, o n N,N'- i hiooxalyl i pamino a id- Thereac; tion between, dithiopxarnide andfthe sodiumlsalt of glycine s llust ati and may e, rep es nted as. to lo'wsi Thereact-ion; is prefer bly carriedou t in a solutionof the d: b a a isfa tome lt Water; s: reaetiontme ium; n mes tin tart es a tho gh;

eral acid to a solution of,t he

tained is not sufficiently pure it may be purified by means well known to the art. Various salts are-conveniently P pared: from: the NiNt-djthiooaalr bi ramin l acids by ron ea iqnalme h d nflame. ins ance t e et: m be; cpn q e l solated: h sti e nden i rea t on m xture wit out inte me iate isolat qn 9 he t s s d- "T e i n a e ex mples. l ustr he. QYWK -Qiir v AMPL -1: N,N'-D,ith'i.q 2;aIylbis-Amjnpacatic Afcid I Sodiumhydroxide solution (0:40 mol. Na OI-I was:v

added! to a mixture of glycine- (30 g., 0.40 mol) and water (500ml.)aand dithiooxamide (24g, 0.20 mol)' was.- thenaddedbveha two hour period while the-temperature of: the. mixture; was: maintained, at;5'5-60'i 'C. i The clear I darlc'brown solution was: filtered at 609' C; andthe filtrate w asia'cidified-v by; adding; hydrochloric acid=( 0.84:rnol -l-ICl).;

withstirring andheatin'g; The: resulting slurry;was cooled-;

to l2 Gland-the crude5N,Nf dithiooxalylbis aminoacetic j 7 acidwastcollec-ted-lona filter andz washed once-with water 3 (75 ml.). The crude product was recrystallized from water (1800 ml.), the hot solution being treated with decolorizing charcoal. The purified N,N'-dithiooxalylbisaminoacetic acid, after drying at 75-80 C., weighed 25.6 g. (54% yield from starting material). Melting point, 225 C. (with decomposition). Calculated for C H N O S N, 11.82%; S, 27.14%; neutral equivalent, Found: N, 11.7%; S, 28.1%; neutral equivalent,

EXAMPLEZ N ,N '-Dithio0xalylbis-2-Aminobutanoic Acid Alpha-aminobutyric acid (102 g., 0.99 mol) and sodium bicarbonate (83.5 g., 0.99 mol) were dissolved in water and to the clear solution was added dithiooxamide (59.5 g., 0.495 mol) in portions with stirring. The mixture was heated at 4050 C. for 7% hours. then stirred overnight without heating. Next day the mixture was again heated at 40-50 C. for 7.5 hours and it was then stirred about64 hours without further heating. The reaction mixture was then filtered and to the filtrate was added dilute hydrochloric acid (365 ml., 1.0 mol HCl). The cooled mixture was filtered and the brown residue of crude N,N'-dithiooxalylbisQ-aminobutanoic acid was dried at 100 C. for three hours. Yield: 100 g. (59%). A portion of the crude product was purified by recrystallizing it from methanol after treating the methanol solution with decolorizing charcoal. Yield of purified N,N'- dithiooxalylbis-2-aminobutanoic acid on recrystallization. 55%. M.P., 219 C. (with decomposition). Calculated for C I-l N O S- N, 9.58%; S, 21.93%;neutral equivalent, 146. Found: N, 9.07%; S, 22.34%, neutral equivalent, 150.

EXAMPLE 3 N,NDiihiooxalylbis-4-Aminobulanoic Acid 2-Pyrrolidone (lactam of gamma-aminobutyric acid, 17.0 g., 0.20 mol) was hydrolyzed by heating it to reflux with concentrated sodium hydroxide solution (0.40 mol NaOl-l). To the resulting clear and cooled solution was added hydrochloric acid (0.40 mol HCl). Then sodium carbonate (10.6 g., 0.10 mol) was added. the mixture was heated, and to the resulting clear solution was added dithiooxamide (12.0 g., 0.10 mol). The reaction mixture was stirred 64 hours and then filtered. Dilute hydrochloric acid (0.20 mol HCl) was added and the orangered precipitate was filtered 05 under reduced pressure and purified by recrystallizing it after treating the ethanol solution with decolorizing charcoal. The purified N,N'- dithiooxalylbis-4-aminobutanoic acid was in the form of pinkish-orange needles and weighed 14.1 g. Yield: 48% M.P.; l67-169 C.' Calculated for C l-I N O S N, 9.58%; S, 21.93%; neutral equivalent, 146. Found: N, 9.3%; S, 22.8%; neutral equivalent, 147. i

0 EXAMPLE 4' N,N'-Dithi0oxalylbis-Z-Aminopemanoic Acid Alpha-aminovaleric acid (98.4 g., 0.84 mol) was mixed with water (1 liter) sodium bicarbonate (70.7 g., 0.84 mol) was added in portions, and the mixture was stirred to complete solution. Dithiooxamide (50.3 g., 0.42 mol) was added and the mixture was stirred for seven hours at 4050 C., then an additional 64 hours without further heating. The small remaining undis'solved residue was filtered ofl, and dilute hydrochloric acid (0.85 mol HCl) was added rapidly to the filtrate. An oil separated which crystallized on stirring. The slurry was stirred over-- night, then chilled and filtered. The air dried, chocolate: brown crude N,N'-dithiooxalylbis-Z-arninopentanoic acid weighed 90.8 g. (Yield: 67%). To purify the crude prod uct it was first dissolved in sodium carbonate solution and" reprecipitated with hydrochloric acid, then reprecipitated (as an oil) by diluting a methanol solution with water.

- Both the aqueous and methanol solutions were treated with decolorizing charcoal. Yellow crystals of purified N,N'-dithiooxa1y1bis-2aminopentanoic acid were obtained by treating the oily precipitate from the methanol solution with chloroform. Yield 16.1 g.; M.P., 198 C. (with decomposition). A second crop of 1.5 g. of the purified product was obtained by working up the mother liquors and washings from the first crop. Calculated for C H N O S N, 8.74%; S, 20.01%; neutral equivalent, 160. Found: N, 8.4%; S, 20.6%; neutral equivalent, 162.

EXAMPLE 5 N,N'-Dithi00xalylbis-3-Aminopropionic Acid Beta-aminopropionic acid (beta-alanine) (112 g., 1.26 mol) and sodium bicarbonate (106 g., 1.26 mol) were dissolved in warm water (800 ml.), and dithiooxamide (75.5 g., 0.63 mol) was added in portions with stirring. More water (400 ml.) was added and the mixture was stirred for 7.5 hours at 45-50 C. then stirred-overnight without heating. The following morning the lighter color of the suspended material indicated that the reaction was complete. The slurry was filtered and dilute hydrochloric acid (1.28 mols of l-lCl) was slowly added to the dark filtrate with stirring, to precipitate crude N,N-dithiooxalylbis-3-aminopropionic acid. 7 The slurry was cooled to 5 C. and filtered, and the precipitate was washed with water and dried 2.5 hours at C. Yield: 105.4 g. of reddish-brown crude N,N-dithiooxalylbis-B-aminopropionic acid (63% of theory) M.P. l92-195 C. Crude N,N'-dithiooxalylbis-3-aminopropionic acid (25 g.) was recrystallized from water (1.1), the hot solution being treated with decolorizing carbon which was filtered ofi before crystallization began. The crystalline product was filtered from the cold solution, washed, and dried 2 hours at 100 C. Yield of orange, purified N,N'-dithiooxalylbis-B-aminopropionic acid 10.7 g. M.P.: 199-202 C. Calculated for C H N O S C, 36.35%; H, 4.58%; N, 10.60%; S.24.26%;neutral equivalent. 132.2.v Found: C, 36.9%; H, 4.9%; N, 10.4%; S, 24.9%; neutral equivalent, 132.

EXAMPLE 6 V N,N'-Dithiooxalylbis 2-Aminopropionic Acid Alanine (alpha-aminopropionie acid) (85- g., 0.95

mol) and sodium bicarbonate (80 g., 0.955 mol) were dissolved in water (500 ml.). Dithiooxamide (57.3 g.,

0.478 mol) was added and the mixture was stirred for 72 hours, during which it was heated intermittently toSO- 55 C. The nearly clear solution was filtered and acidified with hydrochloric acid (1.56 mol l-lCl). The precipitation mixture was chilled and filtered and the wet filter cake was dissolvedin hot methanol (200 ml.),

treated with decolorizing charcoal, and filtered. Water. ml.) was added to the hot filtrate and the mixture was chilled. The crude yellow-brown N,N'-dithiooxalyl-' bis-Z-aminopropionic'acid was filtered ofi, washed and dried at 100 C. Yield: 40.6 g. (32%). A sample darkened above C. and melted with decomposition at 202".C.'--. j V I A portion (5 g.) of the crudeproduct was recrystallized by cooling and adding water to a methanol solution EXAMPLE 7 N,N-Dithiooxalylbis6-Aminohexanoic Acid fi-aminocaproicacid (70.2 g.; 0.54 mol) and sodium carbonate (28.5 g.; 0.27 mol) were dissolved in water (250 ml.). The filtered solution was added to dilIhlOOXe amide (32.2 g., 0.27 mol) and the mixture was stirred and heated ,until the reactants had dissolved. The resulting red-brown solution .was treated with decolorizing charcoal and filtered, hydrochloric acid (0.96 mol HCl) was added, and the filtrate was cooled. The yellow-red precipitate of crude N,N'-dithiooxa1y1bis-6-aminohexanoic acid was filtered off and recrystallized twice from ethanol. The resulting yellow crystals of N,N-dithio oxalylbis-6-aminohexanoic acid melted at 140.5-142 C. Yield, 45%. Calculated for C H N O S neutral equivalent, 174.2. Found: neutral equivalent, 178.2.

EXAMPLE 8 Disodium Salt of N,N'-Dithiooxalylbis-2- Aminoethanesulfonic Acid Dithiooxamide (6 g., 0.05 mol), taurine (Z-aminoethanesulfonic acid, 12.5 g., 0.10 mol) and sodium bicarbonate (8.4 g.; 0.10 mol) were agitated in water (50 ml.) on a steam bath for several hours, during which the reaction mixture darkened and the appearance of the undissolved material changed. The mixture was filtered and the residue washed and air dried. This crude product was recrystallized from Water (8 parts) and the resulting purified disodium salt of N,N'-dithiooxalylbis-2- aminoethanesulfonic acid was yellowish-orange. Yield, 37%. Calculated for C H N O S Na N, 7.36%; S, 33.72%. Found: N, 8.0%; S, 33.4%.

EXAMPLE 9 N,N'-Dithiooxalylbis-Z-Aminoethanesulfonic Acid Disodium salt of N,N'-dithiooxalylbis-Z-aminoethanesulfonic acid was dissolved in water and hydrochloric acid was added to precipitate N,N'-dithiooxalylbis-2- aminoethanesulfonic acid.

It will be understood that the invention embraces other compounds in addition to those whose detailed preparation is described in the preceding working examples. Such compounds are conveniently prepared by following the methods described above and substituting amino acids other than those specifically named. Exemplary of such other amino acids are valine, leucine, norleucine, and isoleucine. Also, it will be understood that salts of these novel N,N'-dithiooxalylbis-amino acids other than the disodium salt, such as dipotassium, nickel, cobalt and copper, etc., salts are conveniently prepared either by the method described in the foregoing examples or by methods well known to those skilled in the art.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

6 I claim: 1. A compound selected from the group consisting of a dibasic acid of the general formula:

in which R represents a lower alkylene radical selected from the group consisting of methylene, polymethylene, and alkyl-substituted methylene radicals, and A represents a monobasic organic acid radical selected from the group consisting of carboxyl and sulfonic radicals, and the salts thereof.

2. N,N-dithiooxalylbis-aminoacetic acid.

3. N,N-dithiooxalylbis-3-aminopropionic acid.

4. N,N-dithiooxalylbis-2-aminoethanesulfonic acid.

5. Disodium salt of N,N'-dithio0xalylbis-2-aminoethanesulfonic acid.

6. Amino acid derivatives of dithiooxamide having the formula R-0o-R I t in which R represents a radical derived from an aliphatic alpha-amino acid by removal of a hydrogen atom from the alpha-amino group.

7. The method which comprises reacting dithiooxamide with the salt of a lower monobasic amino acid of the general formula H N-RA, in which R represents a lower alkylene radical selected from the group consisting of methylene, polymethylene and alkyl-substituted methylene radicals, and A represents a monobasic organic acid radical selected from the group consisting of carboxyl and sulfonic acid radicals, in an inert reaction medium to form the salt of an N,N'-dithiooxalylbis-amino acid.

8. The method which comprises reacting dithiooxamide with the salt of a lower monobasic amino acid of the general formula H N-R-A, in which R represents a lower alkylene radical selected from the group consisting of methylene, polymethylene and alkyl-substituted methylene radicals, and A represents a monobasic organic acid radical selected from the group consisting of carboxyl and sulfonic acid radicals, in an inert reaction medium to form the salt of an N,N'-dithiooxalylbis-amino acid, and thereafter forming the N,N'-dithiooxalylbisamino acid by the addition of a mineral acid.

Kerp et al.: Berichte der Deutsche Chemische Gesellschaft, vol. 30, pages 579-585 (7 pages), 1897.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3 023332 February 2% 1962 Vernon Ho Wallingford It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l line 12 beginning with "Broadly the invention" strike out all to and including "the alpha-amino group," in line 20 same column 1; line 21, for "More particularly" read Briefly Signed and sealed this 26th day of June 1962.,

(SEAL) Attest:

ERNEST W SWI DAVID L. LADD Attesfing Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE CONSISTING OF A DIBASIC ACID OF THE GENERAL FORMULA: 